Papillary renal cell carcinoma (pRCC) is the second most common renal cell carcinoma (RCC) subtype and accounts for 10-15% of all RCCs. Despite clinical need, few pharmacogenomics studies in pRCC have been performed. Moreover, current research fails to adequately include pRCC laboratory models, such as the ACHN or Caki-2 pRCC cell lines. The molecular mechanisms involved in pRCC development and drug resistance are more diverse than in clear-cell RCC, in which inactivation of VHL occurs in the majority of tumours. Drug resistance to multiple therapies in pRCC occurs via genetic alteration (such as mutations resulting in abnormal receptor tyrosine kinase activation or RALBP1 inhibition), dysregulation of signalling pathways (such as GSK3β-EIF4EBP1, PI3K-AKT and the MAPK or interleukin signalling pathways), deregulation of cellular processes (such as resistance to apoptosis or epithelial-to-mesenchymal transition) and interactions between the cell and its environment (for example, through activation of matrix metalloproteinases). Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies. Further studies on novel resistance biomarkers are needed to improve patient prognosis and stratification as well as drug development.

中文翻译：

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乳头状RCC的耐药性：从推测的机制到临床实用性。

乳头状肾细胞癌（pRCC）是第二常见的肾细胞癌（RCC）亚型，占所有RCC的10-15％。尽管有临床需求，但很少在pRCC中进行药物基因组学研究。此外，当前的研究未能充分包括pRCC实验室模型，例如ACHN或Caki-2 pRCC细胞系。与透明细胞RCC相比，参与pRCC发展和耐药性的分子机制更加多样化，在透明细胞RCC中，VHL失活发生在大多数肿瘤中。对pRCC多种疗法的耐药性是通过遗传改变（例如导致受体酪氨酸激酶激活异常或RALBP1抑制异常的突变），信号传导途径（例如GSK3β-EIF4EBP1，PI3K-AKT和MAPK或白介素信号传导途径）失调而发生的，细胞过程的失调（例如对细胞凋亡或上皮到间充质转化的抵抗力）以及细胞与其周围环境之间的相互作用（例如，通过激活基质金属蛋白酶）。增强对耐药机制的了解将有助于发现药物并提供新的有效疗法。需要对新型耐药生物标记物进行进一步研究，以改善患者的预后，分层以及药物开发。